Background: Apoptosis, an important mechanism of cell death, has been demonstrated following traumatic brain injury (TBI) in the rat. Objective: To develop a mouse model of apoptosis induced by TBI for future studies of the effect of anti-apoptotic genes on cell death. Methods: Male C-57 mice (19-21 gm) were anaesthetized, placed in the stereotactic apparatus and subjected to a deceleration-impact brain injury(force = 1000 gm-cm) in the midline between the bregma and interaural line. Control mice were subject to a sham procedure. Behaviour testing was performed prior to and following TBI. The mice were perfused and their brains removed at 6, 24, and 48 hours post-TBI, or 6 hours post sham procedure, cryopreserved and stored at -80°C. Coronal sections (10 μm) were obtained at three positions (stereotactic atlas) through the site of maximum impact. Apoptotic cells were identified on double labelled staining by the presence of both contracted nuclei or chromatin fragmentation by Hoescht staining and in situ end-labelling (ISEL) staining. Apoptotic cells were counted in each section in the corpus callosum and external capsule (site of maximum apoptosis) in all mice. Sections were also double labelled with ISEL and immunofluorescence stain for the neuron specific nuclear protein NeuN, to determine if apoptotic cells were neurons. Results: TBI led to a significant decrease in the behaviour score at 4 hours and a nonsignificant trend to a decreased score at 24 and 48 hours post-TBI. A significant increase(P < 0.001) in the number of apoptotic cells in the corpus callosum and external capsule was seen post-TBI. There were 3.4 ±4.9 apoptotic cells in controls and 24 ±11.2, 34 ±12.7, and 16.2 ±9.6 apoptotic cells 6 h, 24 h, and 48 h post-TBI (n=3 mice/group). The ISEL positive cells were not positive for NeuN, and therefore these apoptotic cells were not likely neurons. They appeared to be glial in origin. Conclusion: In a mouse model of TBI, we have identified a significant increase in apoptosis post-TBI, as compared to controls. The maximal apoptosis occurred in cells (possibly glial) of the corpus callosum and external capsule 24 hours after injury.